A validated LC-MSMS method for the simultaneous quantification of meropenem and vaborbactam in human plasma and renal replacement therapy effluent and its application to a pharmacokinetic study.

A simple method for the simultaneous quantification of meropenem and the recently approved ß-lactamase inhibitor, vaborbactam, in human plasma and renal replacement therapy effluent (RRTE) was developed and validated. This antibiotic combination protects a primary ß-lactam, meropenem, with a new ß-lactamase inhibitor, and expands the limited options for treatment of multidrug-resistant Gram-negative infections. Meropenem, vaborbactam, and the internal standards [2H6]-meropenem and sulbactam in plasma and RRTE were processed using acetonitrile followed by a chromatographic separation on a Poroshell HPH-C18 column with a gradient elution of the mobile phases and monitored using mass spectrometry detection. The calibration range was 0.05 to 100 µg mL-1 for both meropenem and vaborbactam. The intra-day and inter-day precision and accuracy were less than 15% for both meropenem and vaborbactam and the recovery from plasma was 96% for both meropenem and vaborbactam and the recovery from RRTE was 93% and 103% for meropenem and vaborbactam, respectively. This methodology was successfully applied to an ex vivo characterisation study of the effects of renal replacement therapy modalities on the pharmacokinetics of meropenem and vaborbactam (Antimicrob Agents Chemother 62(10), 2018). Graphical abstract.

Analysis of two commercially available bortezomib products: differences in assay of active agent and impurity profile.

The analytical properties of two commercially available bortezomib products (VELCADE(®) and Bortenat) were compared using nuclear magnetic resonance, mass spectrometry, high-performance liquid chromatography, and gas chromatography. The data showed differences between the two products. Based on these data, Bortenat samples contained more active ingredients than indicated by the label (mean, 116.5% and 117.9% of label, in 2-mg and 3.5-mg vials, respectively). In comparison, VELCADE samples contained a mean of 99.3% of active ingredient, which was consistent with the approved specification range (US, 90-110%; EU, 95-105%). Clinical data demonstrate that patients exposed to higher than recommended doses of bortezomib on the standard twice-weekly dosing schedule are likely to have an increased risk of major toxicities. Bortenat 2-mg vials contained an isovaleraldehyde impurity; the origin of this is unknown. Additionally, the ratio of boronic acid to boronic ester differed between Bortenat 2 mg (0.27:1) and 3.5 mg (0.13:1) and VELCADE (0.10:1) samples reconstituted in saline indicating that the Bortenat product is not equivalent to the VELCADE product.

Stability of unused reconstituted bortezomib in original manufacturer vials.

UNLABELLED: BACKGROUND. Bortezomib is a modified dipeptidyl boronic acid analogue used to treat multiple myeloma, mantle cell lymphoma, and, more recently, renal transplantation graft rejection. As per manufacturer recommendations, bortezomib is to be administered within 8 h of preparation or may be stored for up to 8 h in the vial or a syringe following reconstitution. Preserving unused reconstituted bortezomib beyond these 8 h may allow for cost savings. This study aims to examine the stability of unused reconstituted bortezomib when stored at 4°C for up to 15 days. METHODS: Using an LC-MS/MS assay, the concentration of reconstituted bortezomib was measured at predetermined time points following storage at 4°C in the manufacturer vial. Percent bortezomib remaining at a time point was calculated versus initial bortezomib concentration. RESULTS: The concentrations of bortezomib were found to be 51.93 ng/mL±4.60 after 1 day of storage, 57.40 ng/mL±4.77 after 8 days of storage, and 49.43 ng/mL±2.85 after 15 days of storage. The percent of bortezomib remaining was 110.53% and 95.19% after 8 days and 15 days, respectively. CONCLUSION: Unused reconstituted bortezomib is stable for up to 15 days stored at 4°C in the original manufacturer vial. Such use of bortezomib may improve cost efficiency by reducing bortezomib waste.